Edwards, J.

Leung, H.Y.

English

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Edwards, J. and Leung, H.Y. (2007) Editorial comment on: increased 
expression of tumor-associated trypsin inhibitor, TATI, in prostate cancer 
and in androgen-independent 22Rv1 cells. European Urology, 52 (6). pp. 
1680-1681. ISSN 0302-2838 
 
http://eprints.gla.ac.uk/7755/ 
 
Deposited on: 27 October 2009 
 
 
Enlighten – Research publications by members of the University of Glasgow 
http://eprints.gla.ac.uk 
Editorial  for Increased Expression of Tumour Associated Trypsin Inhibitor, TATI in 
Prostate Cancer and in Androgen-Independent 22Rv1 Cells. 
 
Do Trypsinogens And TATIs Have A Role To Play In Prostate Cancer Progression. 
 
J Edwards and HY Leung 
 
It was originally believed that Trypsinogens and pancreatic secretory trypsin inhibitor 
also known as Tumour Associated Trypsin Inhibitor (TATI) were only expressed in 
the pancreas [1].  The function of Trypsinogens once activated are to aid digestion by 
degrading proteins derived from food and activating proenzymes also necessary for 
digestion [2].  TATI inhibit the trypsinogens from digesting the pancreas itself, 
maintaining the balance between these two proteins is necessary for a healthy 
pancreas, as inappropriate activation of trypsinogens is one of the initial steps 
underlying development of pancreatitis [2].   
Over the past 30 years it has been widely accepted that trypsinogens and TATI are 
also expressed out with the pancreas, in particular in the ovaries and gastrointestinal 
tract [3].  Tumours require protelolytic activity for invasion, and trypsin is a potent 
activator of MMPs associated with tissue remodelling and invasion, it is therefore not 
completely surprising that various tumours e.g. ovarian [4], lung [5] and gastric [6] 
are reported to express trypsinogens and TATI [7].  More recently however it has 
been reported that trypsinogens are expressed in human seminal fluid suggesting one 
possible source could be the prostate gland [7].  Trypsin has been demonstrated to be 
expressed in the human prostate gland and indeed be involved both with activation of 
proPSA and degradation of PSA in the seminal plasma [7].  Trypsinogens may 
therefore play a role in reproduction, however if trypsinogens do have a physiological 
function in the prostate, their expression could also contribute to invasion and 
metastasis of prostate cancer.  In deed trypsinogens are highly expressed in high grade 
prostate cancers, and not only by the luminal secretory cells but also by malignant 
cells, suggesting that trypsinogenes may be involved in promoting tumour growth and 
invasion [3].  As trypsinogen and TATI have been reported to be co-expressed in a 
variety of tumours including colorectal [8], ovarian [9] and bladder cancer [10,11] and 
it had previously been reported that expression of trypsinogens was associated with 
prostate cancer it seemed logical to investigate the role of TATI in prostate tumours.  
A paper in this edition by Paju et al. report that TATI is weakly expressed in benign 
prostatic epithelium and expressed with increasing intensity in prostate cancers, the 
intensity of staining in the prostate tumours correlates with Gleason grade.  It is 
hypothesised that as the TATI are expressed in the basal epithelial cells and the 
physiological function of the TATI in the prostate is to inhibit trypsins that have 
leaked from the luminal epithelial cells into the extracellular fluid.  However, it 
remains unclear if TATI co-expressed with trypsinogens in the malignant cells, as is 
observed in other tumour types; the authors suggest that they are expressed in the 
same tumours as both trypsinogens and TATI correlate with increasing Gleason 
grade.  Dual stain experiments would be useful to formally assess this.  Interestingly, 
TATI was found to be secreted by the androgen independent cell line 22Rv1, but not 
in the androgen sensitive LNCaP cell lines, suggesting TATI might be associated with 
a more aggressive phenotype cancer.  It is worth noting that not only is TATI 
expression in the tumour associated with Gleason, but serum levels also correlated 
with PSA and tumour stage.  The series of studies from this group has demonstrated 
that trypsinogens and TATI may be involved in prostate cancer invasion and may also 
be of prognostic significance.  However further work is required to establish the exact 
role these proteins play in progression, and also if they are associated with patient 
survival.  This is an area of research that requires further investigation and should be 
watched with interest. 
 
References 
 
 1.  Haverback BJ, Dyce B, Bundy H, Edmonson HA. Trypsin, trypsinogen and 
trypsin inhibitor in human pancreatic juice. Am J Med 1960;29:421-433. 
 2.  Paju A, Stenman UH. Biochemistry and clinical role of trypsinogens and 
pancreatic secretory trypsin inhibitor. Crit Rev Clin Lab Sci 2006;43:103-142. 
 3.  Bjartell A, Paju A, Zhang WM et al. Expression of tumor-associated 
trypsinogens (TAT-1 and TAT-2) in prostate cancer. Prostate 2005;64:29-39. 
 4.  Hirahara F, Miyagi Y, Miyagi E et al. Trypsinogen expression in human 
ovarian carcinomas. Int J Cancer 1995;63:176-181. 
 5.  Kawano N, Osawa H, Ito T et al. Expression of gelatinase A, tissue inhibitor 
of metalloproteinases-2, matrilysin, and trypsin(ogen) in lung neoplasms: an 
immunohistochemical study. Hum Pathol 1997;28:613-622. 
 6.  Yamashita K, Mimori K, Inoue H, Mori M, Sidransky D. A tumor-suppressive 
role for trypsin in human cancer progression. Cancer Res 2003;63:6575-6578. 
 7.  Paju A, Bjartell A, Zhang WM et al. Expression and characterization of 
trypsinogen produced in the human male genital tract. Am J Pathol 
2000;157:2011-2021. 
 8.  Solakidi S, Tiniakos DG, Petraki K et al. Co-expression of trypsin and 
tumour-associated trypsin inhibitor (TATI) in colorectal adenocarcinomas. Histol 
Histopathol 2003;18:1181-1188. 
 9.  Paju A, Vartiainen J, Haglund C et al. Expression of trypsinogen-1, 
trypsinogen-2, and tumor-associated trypsin inhibitor in ovarian cancer: prognostic 
study on tissue and serum. Clin Cancer Res 2004;10:4761-4768. 
 10.  Hotakainen K, Lintula S, Jarvinen R et al. Overexpression of human chorionic 
gonadotropin Beta genes 3, 5 and 8 in tumor tissue and urinary cells of bladder 
cancer patients. Tumour Biol 2007;28:52-56. 
 11.  Hotakainen K, Bjartell A, Sankila A et al. Differential expression of 
trypsinogen and tumor-associated trypsin inhibitor (TATI) in bladder cancer. Int J 
Oncol 2006;28:95-101. 
 
 


Editorial comment on: increased expression of tumor-associated trypsin inhibitor, TATI, in prostate cancer and in androgen-independent 22Rv1 cells

Enlighten

       Edwards, J. and Leung, H.Y. (2007) Editorial comment on: increased expression of tumor-associated trypsin inhibitor, TATI, in prostate cancer and in androgen-independent 22Rv1 cells. European Urology, 52 (6). pp. 1680-1681. ISSN 0302-2838  http://eprints.gla.ac.uk/7755/  Deposited on: 27 October 2009   Enlighten – Research publications by members of the University of Glasgow http://eprints.gla.ac.uk Editorial  for Increased Expression of Tumour Associated Trypsin Inhibitor, TATI in Prostate Cancer and in Androgen-Independent 22Rv1 Cells.  Do Trypsinogens And TATIs Have A Role To Play In Prostate Cancer Progression.  J Edwards and HY Leung  It was originally believed that Trypsinogens and pancreatic secretory trypsin inhibitor also known as Tumour Associated Trypsin Inhibitor (TATI) were only expressed in the pancreas [1].  The function of Trypsinogens once activated are to aid digestion by degrading proteins derived from food and activating proenzymes also necessary for digestion [2].  TATI inhibit the trypsinogens from digesting the pancreas itself, maintaining the balance between these two proteins is necessary for a healthy pancreas, as inappropriate activation of trypsinogens is one of the initial steps underlying development of pancreatitis [2].   Over the past 30 years it has been widely accepted that trypsinogens and TATI are also expressed out with the pancreas, in particular in the ovaries and gastrointestinal tract [3].  Tumours require protelolytic activity for invasion, and trypsin is a potent activator of MMPs associated with tissue remodelling and invasion, it is therefore not completely surprising that various tumours e.g. ovarian [4], lung [5] and gastric [6] are reported to express trypsinogens and TATI [7].  More recently however it has been reported that trypsinogens are expressed in human seminal fluid suggesting one possible source could be the prostate gland [7].  Trypsin has been demonstrated to be expressed in the human prostate gland and indeed be involved both with activation of proPSA and degradation of PSA in the seminal plasma [7].  Trypsinogens may therefore play a role in reproduction, however if trypsinogens do have a physiological function in the prostate, their expression could also contribute to invasion and metastasis of prostate cancer.  In deed trypsinogens are highly expressed in high grade prostate cancers, and not only by the luminal secretory cells but also by malignant cells, suggesting that trypsinogenes may be involved in promoting tumour growth and invasion [3].  As trypsinogen and TATI have been reported to be co-expressed in a variety of tumours including colorectal [8], ovarian [9] and bladder cancer [10,11] and it had previously been reported that expression of trypsinogens was associated with prostate cancer it seemed logical to investigate the role of TATI in prostate tumours.  A paper in this edition by Paju et al. report that TATI is weakly expressed in benign prostatic epithelium and expressed with increasing intensity in prostate cancers, the intensity of staining in the prostate tumours correlates with Gleason grade.  It is hypothesised that as the TATI are expressed in the basal epithelial cells and the physiological function of the TATI in the prostate is to inhibit trypsins that have leaked from the luminal epithelial cells into the extracellular fluid.  However, it remains unclear if TATI co-expressed with trypsinogens in the malignant cells, as is observed in other tumour types; the authors suggest that they are expressed in the same tumours as both trypsinogens and TATI correlate with increasing Gleason grade.  Dual stain experiments would be useful to formally assess this.  Interestingly, TATI was found to be secreted by the androgen independent cell line 22Rv1, but not in the androgen sensitive LNCaP cell lines, suggesting TATI might be associated with a more aggressive phenotype cancer.  It is worth noting that not only is TATI expression in the tumour associated with Gleason, but serum levels also correlated with PSA and tumour stage.  The series of studies from this group has demonstrated that trypsinogens and TATI may be involved in prostate cancer invasion and may also be of prognostic significance.  However further work is required to establish the exact role these proteins play in progression, and also if they are associated with patient survival.  This is an area of research that requires further investigation and should be watched with interest.  References   1.  Haverback BJ, Dyce B, Bundy H, Edmonson HA. Trypsin, trypsinogen and trypsin inhibitor in human pancreatic juice. Am J Med 1960;29:421-433.  2.  Paju A, Stenman UH. Biochemistry and clinical role of trypsinogens and pancreatic secretory trypsin inhibitor. Crit Rev Clin Lab Sci 2006;43:103-142.  3.  Bjartell A, Paju A, Zhang WM et al. Expression of tumor-associated trypsinogens (TAT-1 and TAT-2) in prostate cancer. Prostate 2005;64:29-39.  4.  Hirahara F, Miyagi Y, Miyagi E et al. Trypsinogen expression in human ovarian carcinomas. Int J Cancer 1995;63:176-181.  5.  Kawano N, Osawa H, Ito T et al. Expression of gelatinase A, tissue inhibitor of metalloproteinases-2, matrilysin, and trypsin(ogen) in lung neoplasms: an immunohistochemical study. Hum Pathol 1997;28:613-622.  6.  Yamashita K, Mimori K, Inoue H, Mori M, Sidransky D. A tumor-suppressive role for trypsin in human cancer progression. Cancer Res 2003;63:6575-6578.  7.  Paju A, Bjartell A, Zhang WM et al. Expression and characterization of trypsinogen produced in the human male genital tract. Am J Pathol 2000;157:2011-2021.  8.  Solakidi S, Tiniakos DG, Petraki K et al. Co-expression of trypsin and tumour-associated trypsin inhibitor (TATI) in colorectal adenocarcinomas. Histol Histopathol 2003;18:1181-1188.  9.  Paju A, Vartiainen J, Haglund C et al. Expression of trypsinogen-1, trypsinogen-2, and tumor-associated trypsin inhibitor in ovarian cancer: prognostic study on tissue and serum. Clin Cancer Res 2004;10:4761-4768.  10.  Hotakainen K, Lintula S, Jarvinen R et al. Overexpression of human chorionic gonadotropin Beta genes 3, 5 and 8 in tumor tissue and urinary cells of bladder cancer patients. Tumour Biol 2007;28:52-56.  11.  Hotakainen K, Bjartell A, Sankila A et al. Differential expression of trypsinogen and tumor-associated trypsin inhibitor (TATI) in bladder cancer. Int J Oncol 2006;28:95-101.   

A tumor-suppressive role for trypsin in human cancer progression.

Biochemistry and clinical role of trypsinogens and pancreatic secretory trypsin inhibitor.

Expression and characterization of trypsinogen produced in the human male genital tract.

Expression of gelatinase A, tissue inhibitor of metalloproteinases-2, matrilysin, and trypsin(ogen) in lung neoplasms: an immunohistochemical study. Hum Pathol

Expression of trypsinogen-1, trypsinogen-2, and tumor-associated trypsin inhibitor in ovarian cancer: prognostic study on tissue and serum.

Overexpression of human chorionic gonadotropin Beta genes 3, 5 and 8 in tumor tissue and urinary cells of bladder cancer patients.

Sankila A et al. Differential expression of trypsinogen and tumor-associated trypsin inhibitor (TATI) in bladder cancer.

trypsinogen and trypsin inhibitor in human pancreatic juice.

Trypsinogen expression in human ovarian carcinomas.

Joanne Edwards

Hing Y. Leung

MUCC (Crossref)

Editorial Comment on: Increased Expression of Tumor-Associated Trypsin Inhibitor, TATI, in Prostate Cancer and in Androgen-Independent 22Rv1 Cells

Editorial comment on: increased expression of tumor-associated trypsin inhibitor, TATI, in prostate cancer and in androgen-independent 22Rv1 cells

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